Cyclosporin A, currently marketed as Neoral® and Sandimmune® (Novartis), is the most widely prescribed drug for the prevention of organ transplant rejection. Cyclosporin A has also demonstrated clinical efficacy in the treatment of autoimmune diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, and Type I diabetes and chronic inflammatory diseases like asthma. Test results in many other preclinical studies indicate utility for cyclosporin A in other therapeutic areas.
Widespread use of cyclosporin A for clinical uses other than prevention of organ transplant rejection is limited, however, due to the drugs narrow therapeutic index. Long term toxicity from chronic administration of cyclosporin A is a serious drawback. Negative consequences associated with chronic treatment with cyclosporin A include nephrotoxicity, abnormal liver function, hirsutism, tremor, neurotoxicity, gastrointestinal discomfort, and other adverse effects. Toxicity associated with cyclosporin A usage has been attributed by many experts working in the immunosuppression therapeutic area as mechanism based. Cyclosporin A inhibits the ubiquitous serine/threonine phosphatase called calcineurin. Attempts to separate the immunosuppressive activity from toxicity through structural modification of cyclosporin A have, for the most part, been unsuccessful. Nevertheless, over the past decade, continued investigation into understanding cyclosporin's toxicity has provided other possible explanations that are independent of calcineurin inhibition.
Published results of recent research (Paolini et al., “Cyclosporin A and Free Radical Generation,” Trends in Pharmaceutical Sciences, 22:14-15 (2001); Buetler et al., “Does Cyclosporin A Generate Free Radicals?” Trends in Pharmaceutical Sciences, 21:288-290 (2000)) suggest that cyclosporin A-mediated generation of reactive oxygen intermediates may be linked with the significant side effects that accompany use of this drug. Results of in vitro and in vivo studies indicate that although cyclosporin A is capable of generating reactive oxygen intermediates, the radicals formed are not derived directly from the cyclosporin A molecule, and are unlikely to stem from mitochondria or from cytochrome P450-mediated metabolism of cyclosporin A.
Novel cyclosporin A analogue, ISATX247, is a potent calcineurin inhibitor (Abel et al., “ISATX247: A Novel Calcineurin Inhibitor,” J. Heart Lung Transplant, 20(2):161 (2001); Aspeslet et al., “ISATX247: A Novel Calcineurin Inhibitor,” Transplantation Proceedings, 33(1-2):1048-1051 (2001)) and has demonstrated a reduced toxicity profile relative to cyclosporin A in animal studies. It remains to be shown if this translates into reduced toxicity in human. In PCT International Publication No. WO 99/18120 to Naicker et al., cyclosporin analogues were claimed, where the MeBmt1 ((4R)-4-((E)-2-butenyl)-4, N-dimethyl-L-threonine) amino acid side chain of cyclosporin A has been structurally modified. Some of the most active compounds claimed in this publication have deuterium incorporated in place of one or more hydrogens in the side chain. Incorporation of deuterium is known to slow down metabolism of compounds in vivo, if hydrogen abstraction is the rate limiting step in the metabolism of the drug (Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends in Pharmaceutical Sciences, 5:524-527 (1984)), and improve the pharmacokinetic properties of the molecule. Deuterium incorporation in cyclosporin A analogues may also block pathways responsible for generation of reactive oxygen intermediates in a manner not currently understood.
Other studies have implicated the role of transforming growth factor-β (TGF-β) in the nephrotoxicity of cyclosporin A (Khanna et al., “TGF-β: A Link Between Immunosuppression, Nephrotoxicity, and CsA,” Transplantation Proceedings, 30:944-945 (1998)). Cyclosporin A induces expression of TGF-β, collagen and fibronectin genes in the kidney. TGF-β has a host of immunosuppressive effects that parallel the effects of cyclosporin A. However, TGF-β also causes the accumulation of extracellular matrix genes by increasing the expression of collagen and fibronectin, which is the hallmark of fibrosis. Because glomerulosclerosis (which occurs with chronic cyclosporin A use) is associated with an increase of extracellular matrix proteins, cyclosporin A-associated nephrotoxicity may be due to TGF-β induction. Novel analogues of cyclosporin A may have different effects on induction of gene expression of proteins like TGF-β and may demonstrate improved therapeutic index.
Therefore, it would be advantageous to have novel cyclosporin derivatives that are safe and effective for the treatment of a variety of diseases.
The present invention is directed to achieving these objectives.